减阻剂对犬缺血心肌保护作用的研究
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摘要
研究背景和目的
目前已证明,通过纯物理作用减低流体阻力的减阻剂(Drag-reducing polymers, DRPs),可以明显降低活体动物血液循环阻力、改善器官血流灌注,尤其可以增加狭窄动脉远端的血流量,提高缺血器官、组织血流灌注水平,从而达到保护缺血器官的作用,我实验室最近的研究结果表明,静脉注射DRP可以明显提高大鼠脊斜肌3级微静脉及微动脉的血流速度和血管直径,可以延长急性心肌梗死大鼠存活时间,大鼠心梗后心功能也有明显改善,其机制可能是DRP可以提高微循环血流量,从而尽可能保护急性缺血心肌；为进一步证实DRP对微循环的作用,求证是否可以提高犬心肌血流储备(Fractional Flow Reserve,FFR),以及是否可能改善犬急性前降支狭窄模型缺血心肌的灌注,试图从纯流体动力学方面提供保护缺血心肌的途径。
方法
取平均分子量为5×106聚氧化乙烯(Polyethylene Oxide, PEO),充分溶解于生理盐水(Normal Saline, NS),再用滤过分子量为50K道尔顿(DA)的透析膜滤除小分子；之后以细玻管和旋压泵为基础建立体外循环减阻模型,检测制得的减阻溶液的减阻性能,记录各流速流量下的压力,建立驱动压与流量的关系曲线。
以急性SD大鼠心肌梗死模型来检测DRP对小动物心肌保护作用,48只340—400g雄性SD大鼠随机分为：假手术组、MI组和DRP组。气管插管,呼吸机辅助呼吸支持下开胸,MI组和DRP组完全结扎冠脉左前降支(Left anterior descending coronary artery, LAD),假手术组除不结扎LAD外其余完全同MI组和DRP组。DRP组给以50ppm经体外减阻检测有效的PEO溶液,以微量泵3.5ml/小时速度持续静脉注射。术后24小时应用超声心动图及实时心肌声学造影评价不同组大鼠左室心功能改变情况。用室壁运动积分指数、射血分数、短轴缩短率、造影积分指数等指标来评价室壁运动情况和心肌灌注情况。
以正常犬经胸心肌声学造影,来检测DRP对正常犬心肌灌注的影响,6条16—24Kg雄性杂种犬先后在基础状态、腺苷负荷状态、静脉以60ml/小时速度泵入250ppmDRP溶液状态及减阻+腺苷负荷状态下分别行经胸心肌声学造影,图像脱机分析。iMCE软件测量不同状态下犬心肌血流速度p值,心肌微循环容积A值,计算出犬心肌血流量A×β,籍此评估DRP对犬心肌血流的影响。
以犬LAD血流限制性狭窄模型评估DRP对狭窄冠脉远端心肌灌注及血流储备分数的影响。6条16—24Kg雄性杂种犬静脉全身麻醉后,在呼吸机辅助呼吸下开胸,结扎LAD近端,左颈总动脉经自制带三通及缩窄器的人工桥血管搭桥至LAD结扎部位以远,经桥血管为LAD结扎部位以远心肌供血。先后在无狭窄状态、无狭窄腺苷负荷状态、血流限制性狭窄、狭窄腺苷负荷状态、狭窄加减阻状态及狭窄减阻+腺苷负荷状态下行开胸心肌声学造影,并通过冠脉内注射腺苷的方法测量基础状态、狭窄状态及狭窄泵入DRP后的状态下血流储备分数(FFR)；超声血流计测量各状态下桥血管血流速度(ml/min)。声学造影图像存3.5寸MO盘或光盘备脱机分析。iMCE软件根据声学造影图像测量不同状态下犬心肌血流速度p值,心肌微血管床容积A值,计算出犬心肌血流量Axp,籍此评估DRP对开胸LAD狭窄犬心肌血流的影响；人工计数正常心肌和桥血管供血心肌声学造影显像延迟心搏数,测量狭窄前后及静脉输入DRP溶液前后FFR变化情况。
结果
体外减阻模型制造的湍流环境下,无论生理盐水还是犬红细胞悬液,加入微量的DRPs即可明显降低流体阻力,在保持旋压泵转速的情况下,流体的流速明显增加,其减阻能力至少在33.61%,相同转速时,毛细管两端压力阶差更低。
超声心动图评估平均分子量为5×106道尔顿的PEO对急性心肌梗死大鼠左心功能的影响和死亡率的影响,结果显示：与对照组比较,DRP对射血分数(36.15±3.60%vs 25.19±2.66%,p<0.05)、左室缩短率FS(40.65+3.32vs24.97±2.66%,p<0.001)等参数具有显著的改善作用。提示：减阻剂可显著改善大鼠急性缺血心肌的灌注和心功能状态。
DRP在健康杂种犬心肌灌注方面也有明显的促进作用,与基础状态比,静脉泵入PEO溶液后,心肌血流量A×β上升达到1倍,与腺苷作用类似,而泵入PEO溶液的基础上在加上腺苷的作用,将使心肌血流量增加达到基础状态的3倍左右,因此,在正常心肌灌注,DRP也有促进作用。
在开胸犬LAD定量狭窄模型上,PEO可以增减狭窄血管的正向血流量,同时还可能有更多的侧枝循环向缺血心肌供血,在反映心肌血流量的Axβ值上有类似经胸犬的增加效果,而在反应血流储备的FFR值上也有大约14%的增加。
由此可见,分子量为5×106道尔顿的PEO作为一种典型的DRPs,具有改善心肌血流,保护缺血心肌的作用,其机理可能与DRP经典的减阻原理和由此继发的生物学效应有关。
Background & Objective
It is shown to us, that the blood-soluble drag reducing polymers(DRPs) can decrease the resistance of the blood flow in vascular, increase the perfusion and tissue oxygenation, when injected in blood at minute concentration in vitro model or vivo animal model of normal or restricted blood flow model. Rencent studies had proved the survival time of rat with acute myocardial infarction can be prolonged by the injection of PEO solution, and the blood flow of ischemic myocardium is improved by the miracle solution. So we hypothesis that the DRPs may improve left ventricular (LV) function in rats with surgically induced MI, furthermore DRPs may have the potential therapeutic effect in treating tissue hypoperfusion caused by atherosclerosis cardiovascular disease (ACVD) or diabetes such as coronary heart disease、shock and peripheral arterial disease. Our study is mean to test the protection on ischemic or acute infracted myocardium of DRPs, and try to find out some conceivable mechanisms of the observed DRPs effects on blood flow, and it is necessary for the process of becoming the chemical into a medicine.
Methods
In our series of test, we characterize and assess efficacy of DRPs for possible usage in atherosclerosis cardiovascular disease (ACVD). The first thing is to make sure that our solution can reduce the restriction of flow in vitro.0.2g commercial polyethylene oxide (PEO) with an average molecule weight of 5×106 Dalton was weighting using a precision balance, Put the PEO powder into a beaker with careful, dissolved with 100ml normal saline, then dialyzed against normal saline to exorcize the low molecule weight and impurities. A hydrodynamic system,which was made of a pump、a thin glass tubing, was developed, two sensor beside the tubing was to measure the driving pressure of flow in the microtubing, was made to test the resistant of NS or red cell suspension containing nano-molarity of PEO.
A rat model of LAD ligation induced MI, were used to find out if the rat heart function as LVEF (left ventricle ejection fraction)、wall motion score index and contrast score index etc were reserved by the injection of PEO.
Latter, the effect on microvascular were examed on a normal dog model, Finally, we test the drag-reducing efficacy of PEO and how much the PEO can ameliorate the volume and speed of the blood flow in microvascular in the dog model of restrict blood flow of LAD. Based on the dp measured at the situation normal without stenosis、normal +AD(adenosine) stress without stenosis、stenosis、stenosis+ AD stress、stenosis+PEO and stenosis +PEO+AD stress, each condition we made MCE(myocardial contrast echocardiography) and record the pressure before and after the stenosis part of the artificial blood vessel under the maximum hyperemia of the myocardium, so we can see if it can improve the FFR
The MCE clips were analysised in iMCE software, the data as plateau video intensity (A) and the refilling velocityof contrast(β) etc. were compared using Analysis of variance of repeated measure data.
Result
The addiction of PEO to vitro circulating system produced a markable reduction in the pressure drop required to achieve a particular flow rate, or at a fixed flow rate,the driving pressure is lower significant than the situation while the PEO is absent; suggesting a drag reduction effect of PEOs with 5×106 MW.
24h following MI, the morbility was significantly different among the sham, MI and DRP groups (P= 0.023), and the LVEF、Wall motion score index and contrast score index were significantly better in DRP group compared with that in NS group (both P<0.001). Comparison using pair t-test between two measurements showed no systematic error (all P>0.05).Viscosity data revealed that at the concentration of 2.5 ppm in our study, DRP had no effect on blood viscosity.
In normal dog model, transthorax MCE shown:with the injection of PEO or adenosine or both,the plateau video intensity (A, represent the capacity of capillaries bed) and the refilling velocityof contrast(β, demonstrate the flow speed of capillaries bed) were significantly improved compared with normal condition.
Compare with the normal LAD, the dog model of restrict blood flow of LAD under the adenosine(AD) stress、single stenosis、stenosis with AD stress、stenosis with PEO injection and stenosis with AD stress and PEO injection, the FFR、blood flow measured by ultrasonic flowmeter、plateau video intensity(A)、refilling velocity of contrast(β)、flow rate of myocardial capillary vessel bed (A×β)and heart beat counts of delayed MCE visualization of the ischemic part of myocardium get a significant improve.
Conclusion
Acute administration of DRPs improved LV function in a rat model of MI possibly by improving microvascular blood flow due to their unique hydrodynamic properties, in dog model,we also proved that DRPs can improve blood flow both normal myocardium and ischemic myocardium. DRPs may offer a novel approach to the treatment of coronary artery ischemic diseases or atherosclerosis cardiovascular disease.
目前已证明,通过纯物理作用减低流体阻力的减阻剂(Drag-reducing polymers, DRPs),可以明显降低活体动物血液循环阻力、改善器官血流灌注,尤其可以增加狭窄动脉远端的血流量,提高缺血器官、组织血流灌注水平,从而达到保护缺血器官的作用,我实验室最近的研究结果表明,静脉注射DRP可以明显提高大鼠脊斜肌3级微静脉及微动脉的血流速度和血管直径,可以延长急性心肌梗死大鼠存活时间,大鼠心梗后心功能也有明显改善,其机制可能是DRP可以提高微循环血流量,从而尽可能保护急性缺血心肌；为进一步证实DRP对微循环的作用,求证是否可以提高犬心肌血流储备(Fractional Flow Reserve,FFR),以及是否可能改善犬急性前降支狭窄模型缺血心肌的灌注,试图从纯流体动力学方面提供保护缺血心肌的途径。
方法
取平均分子量为5×106聚氧化乙烯(Polyethylene Oxide, PEO),充分溶解于生理盐水(Normal Saline, NS),再用滤过分子量为50K道尔顿(DA)的透析膜滤除小分子；之后以细玻管和旋压泵为基础建立体外循环减阻模型,检测制得的减阻溶液的减阻性能,记录各流速流量下的压力,建立驱动压与流量的关系曲线。
以急性SD大鼠心肌梗死模型来检测DRP对小动物心肌保护作用,48只340—400g雄性SD大鼠随机分为：假手术组、MI组和DRP组。气管插管,呼吸机辅助呼吸支持下开胸,MI组和DRP组完全结扎冠脉左前降支(Left anterior descending coronary artery, LAD),假手术组除不结扎LAD外其余完全同MI组和DRP组。DRP组给以50ppm经体外减阻检测有效的PEO溶液,以微量泵3.5ml/小时速度持续静脉注射。术后24小时应用超声心动图及实时心肌声学造影评价不同组大鼠左室心功能改变情况。用室壁运动积分指数、射血分数、短轴缩短率、造影积分指数等指标来评价室壁运动情况和心肌灌注情况。
以正常犬经胸心肌声学造影,来检测DRP对正常犬心肌灌注的影响,6条16—24Kg雄性杂种犬先后在基础状态、腺苷负荷状态、静脉以60ml/小时速度泵入250ppmDRP溶液状态及减阻+腺苷负荷状态下分别行经胸心肌声学造影,图像脱机分析。iMCE软件测量不同状态下犬心肌血流速度p值,心肌微循环容积A值,计算出犬心肌血流量A×β,籍此评估DRP对犬心肌血流的影响。
以犬LAD血流限制性狭窄模型评估DRP对狭窄冠脉远端心肌灌注及血流储备分数的影响。6条16—24Kg雄性杂种犬静脉全身麻醉后,在呼吸机辅助呼吸下开胸,结扎LAD近端,左颈总动脉经自制带三通及缩窄器的人工桥血管搭桥至LAD结扎部位以远,经桥血管为LAD结扎部位以远心肌供血。先后在无狭窄状态、无狭窄腺苷负荷状态、血流限制性狭窄、狭窄腺苷负荷状态、狭窄加减阻状态及狭窄减阻+腺苷负荷状态下行开胸心肌声学造影,并通过冠脉内注射腺苷的方法测量基础状态、狭窄状态及狭窄泵入DRP后的状态下血流储备分数(FFR)；超声血流计测量各状态下桥血管血流速度(ml/min)。声学造影图像存3.5寸MO盘或光盘备脱机分析。iMCE软件根据声学造影图像测量不同状态下犬心肌血流速度p值,心肌微血管床容积A值,计算出犬心肌血流量Axp,籍此评估DRP对开胸LAD狭窄犬心肌血流的影响；人工计数正常心肌和桥血管供血心肌声学造影显像延迟心搏数,测量狭窄前后及静脉输入DRP溶液前后FFR变化情况。
结果
体外减阻模型制造的湍流环境下,无论生理盐水还是犬红细胞悬液,加入微量的DRPs即可明显降低流体阻力,在保持旋压泵转速的情况下,流体的流速明显增加,其减阻能力至少在33.61%,相同转速时,毛细管两端压力阶差更低。
超声心动图评估平均分子量为5×106道尔顿的PEO对急性心肌梗死大鼠左心功能的影响和死亡率的影响,结果显示：与对照组比较,DRP对射血分数(36.15±3.60%vs 25.19±2.66%,p<0.05)、左室缩短率FS(40.65+3.32vs24.97±2.66%,p<0.001)等参数具有显著的改善作用。提示：减阻剂可显著改善大鼠急性缺血心肌的灌注和心功能状态。
DRP在健康杂种犬心肌灌注方面也有明显的促进作用,与基础状态比,静脉泵入PEO溶液后,心肌血流量A×β上升达到1倍,与腺苷作用类似,而泵入PEO溶液的基础上在加上腺苷的作用,将使心肌血流量增加达到基础状态的3倍左右,因此,在正常心肌灌注,DRP也有促进作用。
在开胸犬LAD定量狭窄模型上,PEO可以增减狭窄血管的正向血流量,同时还可能有更多的侧枝循环向缺血心肌供血,在反映心肌血流量的Axβ值上有类似经胸犬的增加效果,而在反应血流储备的FFR值上也有大约14%的增加。
由此可见,分子量为5×106道尔顿的PEO作为一种典型的DRPs,具有改善心肌血流,保护缺血心肌的作用,其机理可能与DRP经典的减阻原理和由此继发的生物学效应有关。
Background & Objective
It is shown to us, that the blood-soluble drag reducing polymers(DRPs) can decrease the resistance of the blood flow in vascular, increase the perfusion and tissue oxygenation, when injected in blood at minute concentration in vitro model or vivo animal model of normal or restricted blood flow model. Rencent studies had proved the survival time of rat with acute myocardial infarction can be prolonged by the injection of PEO solution, and the blood flow of ischemic myocardium is improved by the miracle solution. So we hypothesis that the DRPs may improve left ventricular (LV) function in rats with surgically induced MI, furthermore DRPs may have the potential therapeutic effect in treating tissue hypoperfusion caused by atherosclerosis cardiovascular disease (ACVD) or diabetes such as coronary heart disease、shock and peripheral arterial disease. Our study is mean to test the protection on ischemic or acute infracted myocardium of DRPs, and try to find out some conceivable mechanisms of the observed DRPs effects on blood flow, and it is necessary for the process of becoming the chemical into a medicine.
Methods
In our series of test, we characterize and assess efficacy of DRPs for possible usage in atherosclerosis cardiovascular disease (ACVD). The first thing is to make sure that our solution can reduce the restriction of flow in vitro.0.2g commercial polyethylene oxide (PEO) with an average molecule weight of 5×106 Dalton was weighting using a precision balance, Put the PEO powder into a beaker with careful, dissolved with 100ml normal saline, then dialyzed against normal saline to exorcize the low molecule weight and impurities. A hydrodynamic system,which was made of a pump、a thin glass tubing, was developed, two sensor beside the tubing was to measure the driving pressure of flow in the microtubing, was made to test the resistant of NS or red cell suspension containing nano-molarity of PEO.
A rat model of LAD ligation induced MI, were used to find out if the rat heart function as LVEF (left ventricle ejection fraction)、wall motion score index and contrast score index etc were reserved by the injection of PEO.
Latter, the effect on microvascular were examed on a normal dog model, Finally, we test the drag-reducing efficacy of PEO and how much the PEO can ameliorate the volume and speed of the blood flow in microvascular in the dog model of restrict blood flow of LAD. Based on the dp measured at the situation normal without stenosis、normal +AD(adenosine) stress without stenosis、stenosis、stenosis+ AD stress、stenosis+PEO and stenosis +PEO+AD stress, each condition we made MCE(myocardial contrast echocardiography) and record the pressure before and after the stenosis part of the artificial blood vessel under the maximum hyperemia of the myocardium, so we can see if it can improve the FFR
The MCE clips were analysised in iMCE software, the data as plateau video intensity (A) and the refilling velocityof contrast(β) etc. were compared using Analysis of variance of repeated measure data.
Result
The addiction of PEO to vitro circulating system produced a markable reduction in the pressure drop required to achieve a particular flow rate, or at a fixed flow rate,the driving pressure is lower significant than the situation while the PEO is absent; suggesting a drag reduction effect of PEOs with 5×106 MW.
24h following MI, the morbility was significantly different among the sham, MI and DRP groups (P= 0.023), and the LVEF、Wall motion score index and contrast score index were significantly better in DRP group compared with that in NS group (both P<0.001). Comparison using pair t-test between two measurements showed no systematic error (all P>0.05).Viscosity data revealed that at the concentration of 2.5 ppm in our study, DRP had no effect on blood viscosity.
In normal dog model, transthorax MCE shown:with the injection of PEO or adenosine or both,the plateau video intensity (A, represent the capacity of capillaries bed) and the refilling velocityof contrast(β, demonstrate the flow speed of capillaries bed) were significantly improved compared with normal condition.
Compare with the normal LAD, the dog model of restrict blood flow of LAD under the adenosine(AD) stress、single stenosis、stenosis with AD stress、stenosis with PEO injection and stenosis with AD stress and PEO injection, the FFR、blood flow measured by ultrasonic flowmeter、plateau video intensity(A)、refilling velocity of contrast(β)、flow rate of myocardial capillary vessel bed (A×β)and heart beat counts of delayed MCE visualization of the ischemic part of myocardium get a significant improve.
Conclusion
Acute administration of DRPs improved LV function in a rat model of MI possibly by improving microvascular blood flow due to their unique hydrodynamic properties, in dog model,we also proved that DRPs can improve blood flow both normal myocardium and ischemic myocardium. DRPs may offer a novel approach to the treatment of coronary artery ischemic diseases or atherosclerosis cardiovascular disease.
引文
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[21]Mostardi R A, Greene H L, Nokes R F, et al. The effect of drag reducing agents on stenotic flow disturbances in dogs[J]. Biorheology,1976,13(2): 137-141.
[22]Pacella J J, Kameneva M V, Csikari M, et al. A novel hydrodynamic approach to the treatment of coronary artery disease[J]. Eur Heart J,2006,27(19): 2362-2369.
[23]Pijls N H, Van Gelder B, Van der Voort P, et al. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow[J]. Circulation,1995,92(11):3183-3193.
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[27]Ozdemir M, Yazici G E, Turkoglu S, et al. Metoprolol does not effect myocardial fractional flow reserve in patients with intermediate coronary stenoses[J]. Int Heart J,2007,48(4):477-483.
[28]Kameneva M V, Fink M P. Hemorrhagic shock, drag-reducing polymers and 'spherical cows'[J]. Crit Care,2005,9(3):304-305,304-305.
[29]Burger Ed C L P T. Studies of drag reduction conducted over a broad range of pipeline conditions when flowing Prudhoe Bay crude oil[J]. Rheol,1980: 24-603.
[30]Chen X, Zha D, Xiu J, et al. A new hydrodynamic approach by infusion of drag-reducing polymers to improve left ventricular function in rats with myocardial infarction [J]. Int J Cardiol,2011,147(1):112-117.
[31]Kameneva MV. Effect's of Blood Soluble Drag Reducing Polymers on Macro and Microcirculation.[C].2004.
[32]Gutierrez G, Fuller S P. Of hemorrhagic shock, spherical cows and Aloe vera[J]. Crit Care,2004,8(6):406-407.
[33]Chen X, Zha D, Xiu J, et al. A new hydrodynamic approach by infusion of drag-reducing polymers to improve left ventricular function in rats with myocardial infarction[J]. Int J Cardiol,2011,147(1):112-117.
[34][34] Zhao R, Marhefka J N, Antaki J F, et al. Drag-reducing polymers diminish near-wall concentration of platelets in microchannel blood flow[J]. Biorheology,2010,47(3-4):193-203.
[35]Marascalco P J, Blair H C, Nieponice A, et al. Intravenous injections of soluble drag-reducing polymers reduce foreign body reaction to implants [J]. ASAIO J,2009,55(5):503-508.
[36]Bland J M, Altman D G. Statistical methods for assessing agreement between two methods of clinical measurement[J]. Lancet,1986,1(8476):307-310.
[37]Polimeni P I, Ottenbreit B T. Hemodynamic effects of a poly(ethylene oxide) drag-reducing polymer, Polyox WSR N-60K, in the open-chest rat[J]. J Cardiovasc Pharmacol,1989,14(3):374-380.
[38]Smyth D D, Blandford D E, Jones D R, et al. Separan AP-273 and renal function:a novel natriuretic substance[J]. Can J Physiol Pharmacol,1987, 65(9):2001-2003.
[39]Smyth D D, Polimeni P I. Drag-reducing polymers:a novel class of diuretic and natriuretic compounds[J]. Cardiovasc Drugs Ther,1990,4(1):297-300.
[40]Faruqui F I, Otten M D, Polimeni P I. Protection against atherogenesis with the polymer drag-reducing agent Separan AP-30[J]. Circulation,1987,75(3): 627-635.
[41]Sawchuk A P, Unthank J L, Dalsing M C. Drag reducing polymers may decrease atherosclerosis by increasing shear in areas normally exposed to low shear stress[J]. J Vasc Surg,1999,30(4):761-764.
[42]Muller J M, Chilian W M, Davis M J. Integrin signaling transduces shear stress--dependent vasodilation of coronary arterioles[J]. Circ Res,1997,80(3): 320-326.
[43]Marhefka J N, Velankar S S, Chapman T M, et al. Mechanical degradation of drag reducing polymers in suspensions of blood cells and rigid particles[J]. Biorheology,2008,45(5):599-609.
[44]Marhefka J N, Marascalco P J, Chapman T M, et al. Poly(N-vinylformamide)-A drag-reducing polymer for biomedical applications [J]. Biomacromolecules,2006,7(5):1597-1603.
[45]Daly A R, Sobajima H, Olia S E, et al. Application of drag-reducing polymer solutions as test fluids for in vitro evaluation of potential blood damage in blood pumps[J]. ASAIO J,2010,56(1):6-11.